The present invention is directed to novel PBT and DABO derivatives. In one particular embodiment, the invention is directed to novel PBT and DABO derivatives that exhibit spermicidal activity.
Human immunodeficiency virus (HIV), the etiologic agent of acquired immunodeficiency syndrome (AIDS), is the fastest growing cause of death in women of reproductive age. Heterosexual transmission accounts for 90% of all HIV infections worldwide and constitutes a growing proportion of new HIV infections in the United States. By the year 2000, thirteen million women will be infected with HIV out of a worldwide total of 40 million HIV-infected individuals. In the absence of an effective prophylactic anti-HIV vaccine or antiretroviral therapy, female-controlled vaginal microbicides for curbing mucosal and perinatal HIV transmission are needed.
There is concern that worldwide use of detergent spermicides, such as nonoxynol-9 (N-9) might actually increase the risk of HIV transmission. N-9 has been used for more than 30 years in over-the-counter gels, foams, creams, sponges, films, and foaming tablets designed to kill sperm. Because N-9 has been shown to inactivate HIV in vitro, it is the only topical microbicide currently under consideration for protection against sexually transmitted HIV infection in women. However, the main drawback of using N-9 is its detergent-type effect on epithelial cells. Frequent use of N-9 as a vaginal contraceptive has been associated with an increased risk of cervicovaginal infection, irritation, or ulceration. Since continued use of N-9 can alter the vaginal flora and promote opportunistic infections, it can enhance the susceptibility of the ectocervical epithelium and endocervical mucosa to HIV infection. Furthermore, recent clinical trials have shown that vaginal contraceptives containing N-9 had no effect on the transmission of HIV/AIDS and other STDs when provided as part of an overall prevention program to prevent heterosexual transmission of HIV/AIDS. See, for Example, Roddy et. al., 1998, N.Eng.J Med. 339:504-510; Hira et.al., 1997, Int. J. STD AIDS 8:243-250)
New, effective, safe, and female-controlled topical microbicides lacking detergent-type membrane toxicity should have clinical advantage over the currently available vaginal microbicides. Physiological fertilization depends on the ability of the ejaculated sperm to swim, bind the zona pellucida, and penetrate the egg. Each of these activities is primarily dependent on sperm motility. Therefore, adding spermicidal function to antiretroviral drugs of choice, such as non-nucleoside inhibitors (NNIs), could be an effective way to curb heterosexual vaginal transmission of HIV as well as prevent conception.
The present invention provides novel nonnucleoside inhibitors (NNIS) which are phenethyl-5-bromopyridylthiourea (PBT) and dihydroalkoxybenzyloxopyrimidine (DABO) derivatives. These compounds are useful as sperm immobilizing or contraceptive agents. To applicants"" knowledge, PBT and DABO derivatives have not previously been studied and recognized as having any contraceptive, e.g., spermicidal, or sperm-inmobilizing, activity.
The invention provides halogenated PBT derivatives having the chemical structure (I), or a pharmaceutically acceptable salt thereof: 
where R, R16, R2, R3, and R4 are independently hydrogen, F, Cl, Br, or I, and where at least one of R, R1, R2, R3, and R4 is F, Cl, Br, or I.
The invention also provides a novel DABO derivative compound comprising the formula (III): 
where R1 and R2 are alike or different, and are hydrogen, halo, alkyl, alkenyl, hydroxy, alkoxy, thioalkyl, thiol, phosphino, ROH, or RNH group, where R is alkyl; Y is S or O; and R3 is alkyl, alkenyl, aryl, aralkyl, ROH, or RNH2 group, where R is alkyl; or a pharmaceutically acceptable salt thereof.
The invention additionally provides a method of inhibiting conception in a mammal. The method comprises contacting mammalian sperm with an effective spermicidal amount of a novel halogenated PBT derivative or a novel DABO derivative of the invention.
Another aspect of the invention is a method for inhibiting the motility of sperm. The method comprises contacting sperm with a sperm mobility-inhibiting effective amount of a halogenated PBT derivative or a DABO derivative of the invention.
The invention also provides a composition comprising an effective spermicidal amount of a spermicidal agent, and a pharmaceutically acceptable carrier, diluent, or vehicle. The spermicidal agent comprises a halogenated PBT derivative or a DABO derivative of the invention.
The invention also provides a spermicidal article comprising a halogenated PBT derivative or a DABO derivative of the invention.
Other aspects of the invention will become apparent to those skilled in the art upon review of the following drawings, detailed description, examples and claims.